Osteoporosis encompasses a broad range of clinical syndromes having varying etiologies. In postmenopausal women, for example, two distinct types of osteoporsis have been identified. Type I osteoporosis occurs mainly in the early postmenopausal period from about age 50-65. It is characterized by excessive resorption, primarily in trabecular bone. Vertebral fractures are common. If given prior to significant bone loss, treatment which decreases or prevents bone resorption (such as with estrogen or calcitonin) is considered effective therapy.
Type II osteoporosis (a.k.a. senile osteoporosis) occurs essentially in all aging women and, to a lesser extent, in men. It is characterized by proportionate loss of cortical bone as well as trabecular bone. Here decreased bone formation plays a major role, if not a more important role than increased bone resorption. Fractures of the hip are characteristic of this type of osteoporosis.
Currently approved therapeutic agents for osteoporosis are antiresorptives. As such, while they may prevent further loss in patients with Type I osteoporosis, they are not as effective in reversing osteoporosis of either Type I or Type II or in halting Type II osteoporsis. See The American Journal of Medicine, Vol. 91 (Suppl 5B) 37S-41S; The American Journal of Medicine, Vol. 91 (Suppl 5B) 10S-13S; and The American Journal of Medicine, Vol. 91 (Suppl 5B) 23S-28S. In addition, the most widely accepted preventive agent for osteoporosis currently in use is estrogen therapy, which is not really an acceptable therapeutic agent for women with a history of or at risk for breast or endometrial cancers (estrogen dependent tumors) or for men with osteoporosis.
Insulin-like Growth Factor I (IGF-I) is a 70 amino acid peptide belonging to a family of compounds under the class name somatomedins and retains some structural and biologically similarities to insulin. The somatemedins' activity lie on a spectrum from hypoglycemic effects similar to insulin to growth promoting effects which are exemplified by growth hormone. IGF-I predominately induces growth and cell proliferation. IGF-I has also been demonstrated to specifically bind to receptors on rat osteoblast-like bone cells (Bennett et al, Endocrin. 115(4):1577-1583, 1984). IGF-I is routinely fabricated in the liver and released for binding to carrier proteins in the plasma (Schwander et al, Endocrin. 113(1):297-305, 1983), which bound form is inactive. In addition, there is a biofeedback regulating loop involving the somatomedins and growth hormone such that higher somatomedin concentrations inhibit growth hormone release which results in lesser production of endogenous IGF-I.
IGF-I infused into rats has been shown to result in markedly greater increases in body weight gain compared to controls, with increases in tibial epiphyseal width and thymidine incorporation into costal cartilage (Nature 107: 16-24, 1984) and directly stimulate osteoblasts to result in a greater number of functional osteoblasts. IGF-I is also mentioned as the vehicle through which growth hormone's effects on bone is mediated in Simpson, Growth Factors Which Affect Bone, Physiol. 235, TIBS, December 12, 1984.
Nevertheless, it is important to note that the foregoing pre-clinical studies were conducted with fetal or newborn rat cells. It is highly likely that such "young" cells are more responsive to IGF-I (as well as other influences) than older cells, especially those in the elderly with established osteoporosis or those with drug induced or environmentally induced defects leading to reduced bone density. Furthermore, in J. Bone and Mineral Res., Vol 6, Suppl 1, Abstr. 549, p. S-221, August 1991, the authors report that IGF-I has virtually no effect on cortical bone of oovariectomized rats.